Pancreatic cancer is the fourth leading cause of cancer related death in the United States. It also has the worst mortality rate of all malignancies. This is due to the lack of a method for early detection and the lack of effective treatment for patients with advanced disease. During our previous grant period, we identified and validated Aurora A and Aurora B kinases as drug targets in pancreatic cancer. We also developed a series of aurora kinase inhibitors (AKIs) that showed potent activities in preclinical pancreatic cancer models. The inhibitors were licensed to a biotech company and an optimized lead (called MP529) will enter clinical trials this fall. In this renewal of our R01 we are now proposing to take our AKI work to the next level. Phase I clinical trial results from some early aurora kinase inhibitors have so far indicated that patient response rates to aurora kinase inhibitors might be modest at best. Based on the experience with other kinase targeted therapies, we hypothesize that there exist genetic alterations (contexts of vulnerability) in cancer cells that dictate their sensitivity to AKIs. By identifying such contexts of vulnerability we will be able to develop either new biomarkers for selecting patient populations for AKI therapies or new AKI based combination therapies that increase patient response. In this proposal, we seek to: a) identify the genetic alterations in patients'tumors which would make the tumors more sensitive to AKIs because we could then identify and treat only those patients who would benefit from AKIs, e.g. have biomarker for response to AKIs;b) validate secondary targets which, when inhibited, will increase the sensitivity of cancer cells to treatment with AKIs and;c) develop new agents to hit those secondary targets to sensitize patients'tumors to AKIs. The specific aims of this proposal are as follow: Aim 1: to identify and validate genes in pancreatic cancer cells which, when deleted or when their expression is inhibited will lead to increased sensitivity of pancreatic cancer cells to aurora kinase inhibitors. This will be done using high throughput small interfering RNA (siRNA). Aim 2: to validate the clinical relevance of the gene targets identified in Aim 1 by comparative genomics hybridization (CGH) and tissue microarray (TMA) based copy number and protein expression analyses of pancreatic tumor tissues taken directly from patients. Aim 3: to identify agents that suppress or knock out genes identified in Aims 1 and 2 and evaluate their anti-cancer activity in combination with AKIs in preclinical models. This proposal work should help optimize the utility of promising aurora kinase inhibitor for the treatment of patients with pancreatic cancer. Pancreatic cancer is the fourth leading course of cancer death in the United States. Every year, about 37,000 people in the United States will be found to have pancreatic cancer and over 33,000 patients will die of the disease. The current proposal seeks to identify potential biomarkers that would predict patients'response to aurora kinase inhibitors and to develop novel anti-cancer agents that would sensitize pancreatic cancer patients'tumor to the treatment of aurora kinase inhibitors. The results generated from this project therefore have the potential to directly benefit pancreatic cancer patients with improved treatment and the general public with reduced healthcare cost.